Abstract: Fatty acid bile acid conjugates (FABACs) have been found to affect skin by enhancing ATP-binding cassette (ABCA1) cholesterol transporter and competitively inhibiting stearoyl-CoA desaturase (SCD1) enzyme. Based on the mechanisms involved, detailed here, the authors developed a new FABAC and tested it in vitro. Results suggest its potential as an anti-aging and anti-acne active.

Fatty acid bile acid conjugates (FABACs) are a family of small synthetic molecules that initially were developed as oral drugs to reduce fat build-up and accumulation in the liver. The structure-activity rationale is that the saturated fatty acid acts as a cholesterol solubilizing agent while the bile acid acts as a vehicle to enable secretion into bile and penetrate into the enterohepatic circulation. The amide bond further enhances stability against intestinal degradation. In the skin, however, cholesterol metabolism differs dramatically. Skin renewal is maintained by controlling the balance between proliferation, differentiation and apoptosis of epidermal cells, and it has been shown that this program of epidermal differentiation in keratinocytes is altered when cholesterol-enriched domains in the plasma membrane are disrupted.

Leveraging the innovation of FABACs in health care, the authors developed a specific FABAC based on a cholesterol-solubilizing moiety, i.e., saturated fatty acid, and a bile acid (cholic acid) as the vehicle to enable secretion into bile and entry into the enterohepatic circulation for potential skin benefits. This compound was chosen for its relatively low molecular weight and lipophilicity, allowing it to penetrate skin, affect cholesterol on the cell membrane level and facilitate other mechanisms. Previous proteomic data has proven the activities of FABACs in enhancing ATP-binding cassette (ABCA1) cholesterol transporter and competitively inhibiting stearoyl-CoA desaturase (SCD1) enzyme. Therefore, it was hypothesized that the developed FABAC would affect skin in similar ways.

In this paper, the mechanisms of ABCA1 cholesterol transporter and SCD1 enzyme in the skin are detailed first, highlighting the structure-activity relationships (SARs) involved. Following this, in vitro screenings of the FABAC active are described; screenings determined the level that activity was occurring. Interestingly, compiled results suggest activities comparable to retinoic acid—the only drug currently prescribed for skin aging and known for anti-acne effects (see Page 46 for more on this ingredient). However, retinoic acid acts through nuclear receptors, whereas the new FABAC is believed to act on cellular membrane transporters and competitively inhibit enzymes by depleting cholesterol from the membrane, thereby changing membrane fluidity and the exposure of membrane-anchored receptors. This milder yet effective mode of action is an attractive option due to its larger margin of safety.

Cholesterol in Skin

The skin is a site of active lipid synthesis. In the stratum corneum, aliphatic lipids are synthesized de novo in the epidermis via phospholipids, and cholesterol is synthesized from acetate within hours after induction; cholesterol esters are produced three to seven days later. The skin’s lipid profile affects its ability to serve key functions, such as acting as a barrier against insult and preventing water loss from the body.

The up-regulation of involucrin production, as a result of the down-regulation of keratins 1 and 10, can be explained as a compensation mechanism that allows the epidermis to maintain its integrity in spite of the attenuated differentiation.

Table 3. Conditions Leading to Acne and Anticipated Activity of the Specified FABAC

The physiological conditions leading to acne and the anticipated activity of the specified FABACa based on its structure, SARs with similar FABACs, and data generated from the gene expression study.

Figure 1. Synthesis path of cholesterol in skin

In the stratum corneum, aliphatic lipids are synthesized de novo in the epidermis via phospholipids, and cholesterol is synthesized from acetate within hours after induction.

Figure 2. Illustration of lipid raft

Illustration of a lipid raft; region 1) is standard lipid bilayer while region 2) is a lipid raft